Au (I)-based drugs - sodium aurothiomalate and aurothioglucose – are selective and potent zinc-finger inhibitors of PARP-1

Poly(ADP-ribose) polymerase-1 (PARP-1) is a multidomain enzyme essential
for the DNA damage response; its inhibition can lead to cancer cell death.
Recruitment of PARP-1 to sites of genomic damage is mediated by its zinc
finger domains. In this study, we investigated the inhibition of PARP-1’s
DNA-dependent activation by three Au(I)-based drugs, presumable
zinc-ejectors. We found that aurothioglucose and sodium aurothiomalate
selectively inhibited PARP-1’s DNA-dependent activity, with IC50 values in
the nanomolar range, while preserving its DNA-independent activity.
Furthermore, in a BRCA-mutated cell line, both compounds effectively
suppressed DNA replication, with half-maximal effective concentrations
(EC50) also in the nanomolar range. These findings highlight the potential
of selective, zinc finger–targeting PARP-1 inhibitors as promising
therapeutic agents.